4-pyridylcarbinolamine anti-malarials

ABSTRACT

A series of 4-pyridylcarbinolamines is herein disclosed which has value in treatment of plasmodial infections. The compounds have substituted phenyl groups at positions 2- and 6- on the pyridine moiety, with the electronegative substituents (the same, or different) present on the phenyl nuclei. The syntheses of such series is described, together with a method for separation of racemates of a representative 4-pyridyl-carbinolamine type.

United States Patent 1 3,764,604 Ash et al. Oct. 9, 19734-PYRIDYLCARBINOLAMINE [56] References Cited ANTI-MALARIALS inventors:Arthur B. Ash; Calvin L. Stevens, both of Detroit; Anica Markovac,Lathrup Village, all of Mich.

Assignee: The United States of America as represented by the Secretaryof the Army, Washington, D.C.

Filed: June 7, 1971 Appl. No.: 150,745

Related Application Data Continuation-impart of Ser. No. 784,467, Dec.17, 1968, Pat. No. 3,600,396.

US. Cl. 260/293.53, 260/293.69, 260/295 R, 260/296 R, 260/296 T, 260/999Int. Cl c07d 39/06 Field of Search 260/293.53, 293.69, 260/296 R OTHERPUBLICATIONS Wiselogle, A Survey of Antimaleria Drugs 1941 to l- 945,Edwards, Ann Arbor, Mich. (1946).

Primary ExaminerHenry R. Jiles Assistant ExaminerG. Thomas ToddAttorney-Miller, Morriss, Pappas & McLeod 5 7 ABSTRACT type.

9 Claims, N0 Drawings l 4-PYRIDYLCARBINOLAM'INE ANTI MAILA R'I'A'LSCROSS REFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of Application Ser. No. 784,467, filed Dec. 17,I968, now US. Pat. No. 3,600,369.

BACKGROUND OF THE INVENTION The subject invention relates to 4-pyridinecarbinolamines having enhanced antimalarial activity, and tomeans for achieving the synthesis of such compounds. Specifically, thenew products are fer structurally from those known'hitherto, and provideadvantages in chemotherapeutic index and also in po-' tential foravoiding unwanted side effects such as phototoxicity.

DETAILED DESCRIPTION OF THE INVENTION The subject series ofcarbinolamine typesisconveniently represented by the Structure I, andtopharmaceutically-acceptable acid-addition salts thereof which also formbasis for the invention. It is'in tended that there be included theseveral isomeric forms possible in Structure I, moreover.

The above (Structure I) establishes the new antimalarial agents aspyridine-4-carbinols bearinga basicallysubstituted unit in thealpha-position, and-the same or different substituted-phenyl groupingson the pyridine ring system. This comes from definition of terms,wherein,

=hydrogen, while R =hydrogen or (lower alkyl) and R =(lower alkyl), thesame or differentfrom R R+R-,=(CI-I with R,=H;

III R1 N-Cg: CHN c (crrm cu,

R: CH)-CH and ther the same or different. The term lower alkyl as usedherein means one to carbon atoms which can be straight, branched chainor cyclic with repeating methylene groups.

The patterns of worth for representatives of Structure l'have beenestablished through use ofhighly standardized'tests in experimentalmammals. The preferred mode for administering these compounds consistsin use of non-toxic acid-addition salts, inclusive of. those formed from(I) and acids such as hydrochloric, hydrobromic, sulfamic, sulfuric,phosphoric, citric, tartaric, methanesulfonic, isethionic, aceturic,malic, fumaric, beta-resorcylic, or pamoic acid. Said salts may beadministered orally in the formof tablets, capsules or dragees whenadmixed with solid excipients such as lactose, sucrose, starch,microcrystalline cellulose, magnesium stearate, or tale. The foregoingcompositions are preferred means for oral administration over use offlavoredsyrups or tinctures containing the antimalarial drug. Underspecial circumstances, parenteral adrninistrationmay be indicated,employing an aqueous solutionof the agent or an Oleaginous formulationof' it. Aqueous solutions could be prepared in water, physiologicalsaline, Ringers solution, or the like, either with or without buffers.Oleaginous formulations may be made innatural oils (as, peanut oil orolive oil), or in benzyl benzoate, for example. The several possibleisomeric forms for Structure I are to be included among the preferredantimalarials, and advantage may accrue in the choice of'one or other ofthese.

This invention includes mode for the chemical synthesis of the seriesdefined by Structure I. It represents an extension and'amp'lification ofart which certain of the present Inventors have divulged in theircopending Patent Application of Ser. No. 784,467 on AntimalarialCompounds and'Process for the Preparation Thereof, now US Pat. No.3,600,396. Charts 1 through 3 have been used to outline the synthesis ofthe subject carbinolamines. As is apparent from the structure, suchseries occur in optically active form. A representative type, where twooptical centers are present, has been separated into a pair ofracemates, one of which has appreciable antimalarial activity. Inanother case, where only one optical center is present, the racemic pairresulting from synthesis, was subsequently separated into thedextrorotary and laevorotary forms with resulting significantantimalarial differences.

The course of synthesis of alpha- (dialkylaminomethyl)-2,6-diaryl4-pyridinecarbinols (Structure 1, R,=H, having R and R as lower alkylgroupings, with (Ar) and (Ar),; as substituted phenyl groups) isoutlined in Chart 1. The requisite products have Formula III. Thismethod was applicable to types having (Ar) and (Ar)., either the same ordiffering aryl functions. The intermediate oxirane could be caused toreact with various primary amines (R =I-I; R =alkyl) or secondary amines(R and R each, being alkyl groupings, the same or different. Saidcarbinolamines (Formula III) were most'satisfactorily administered inthe (Ar)-,and (Ar) are Substituted-phenyl groupings, ei-

form of acid-addition salts.

The requisite alpha-( 2-piperidyl)-2,6-diaryl-4- pyridylcarbinols(Formula IV) were prepared from the intermediate 2,6-diaryl-isonicotinic acids (Formula II) in the manner outlined in Chart2. The same intermediate (viz., the isonicotinic acid type II) wasemployed in the synthesis of alpha-(Z-quinuclidinyl)-2,6-diaryl-4-pyridinecarbinols (Formula V), as shown in Chart 3. As in the instanceof the less complex carbinolamines (Chart 1), so also the products(Formula IV and V) of transformations given in Chart 2 and Chart 3 weremost conveniently used in the form of their acid-addition salts.

The Examples hereinafter given further illustrate the preparation of4-pyridylcarbinolamines of Formula I, but in no way limit the scope ofthe lnvention to Formulas lll, 1V and V as representative thereof. Saidrepresentations are not to be viewed as restricted to a singlestereoisomeric form. All temperatures are given in degrees Celsius (C.),and metric units are employed for weights and measures.

EXPERIMENTAL Synthetic paths leading to the Examples have been shown inCharts 1 through 3, and all are illustrative of the Invention relatingto 4-pyridylcarbinolamines having Formula I. Alternative routes foracquiring certain intermediates are apparent to those skilled in theart, and certain of these are revealed in the examples. For convenience,the Examples have been separated into Sections to ensure clarity. Thus,the common intermediate 2,6-diaryl isonicotinic acids (Formula 11) havebeen illustrated in Examples 1 through 11. Examples 12 through 36 areillustrative of the modes for synthesis of the carbinolamines of Formula111, and Example 37 relates to compound of Formula IV. Example 38provides an illustration of the alpha-(2-quinuc1idinyl)-2,6-diaryl-4-pyridinecarbinol type of Formula V.

A. 2,6-DIARYL ISONlCOTINlC ACIDS I Example l.2,6-bis(4-chlorophenyl)isonicotinic Acid 1. N-(4-chlorophenacyl)pyridinium Bromide To a solution of 12.3 g. (0.155 mole) pyridine in 70ml. ethanol, there was added 35.2 g. (0.150 mole) 4- chlorophenacylbromide. The mixture was refluxed for minutes, cooled, and then the saltcaused to separate by gradual addition of ethanol-ether and ether. Theresulting crude product was recrystallized from ethanol to give 45 g.(95 percent yield) of white solid mp. 208-210.

2. 3-(4-Chlorobenzoyl) acrylic acid.

This intermediate was produced by the interaction of chlorobenzene withmaleic anhydride under Friedel- Crafts conditions, as described in theliterature by Papa, et al. J. Amer. Chem. Soc., 70, 3356 (1948).

3. 2,6-bis(4-Clorophenyl) isonicotinic acid.

A stirred mixture comprised of 2.11 g. (10 mmole)3-(4-chlorobenzoyl)acrylic acid, 3.13 g. (IOmmole) N-(4-chlorophenacyl)pyridinium bromide, 10 ml. of acetic acid, 1 ml. acetic anhydride, and 6g. ammonium acetate was refluxed for 4 hours. The hot mixture wasdiluted with ca. 30 to 40 ml. water and allowed to cool, then filtered.The solid was washed (water) and dissolved in 150 ml. of hot 2 percentaqueous potassium carbonate solution. Unwanted substances were removedby multiple extractions with chloroform, then ether, and treatment withcharcoal in the hot. The product was precipitated by acidification topH2, collected, washed with water, and crystallized from ethanol. A 54percent yield (1.85 g.) of 2,6-bis (4- chlorophenyl) isonicotinic acid,m.p. 266- 288, was obtained.

Anal. Calcd for C H CI NO C, 62.81; H, 3.22; N, 4.07. Found: C, 62.47;H, 3.53; N, 4.30.

the foregoing example were replaced with 16ml of methanol, and themixture was refluxed for five hr.

. '65 Alternatively, the acetic acid and acetic anhydride in (Solidappeared after 30 min to 1 hr). The mixture was filtered, and theprecipitate was washed with 10 ml. of cold methanol. The solid was thendigested in 30 ml of glacial acetic acid until the fine precipitatebecame granular (10 15 min). The mixture was diluted with ml of water,cooled and filtered. The solid was washed with water and crystallized(x2) from propanol- 2 to yield 60 percent of product, mp 286 288.Example 2. 2,6-bis (Phenyl)isonicotinic Acid 1. N-(Phenacyl) pyridiniumbromide Phenacyl bromide (10 g., 0.05 mole) was added to a solution of4.1 g., (0.052 mole) pyridine in 20 ml. ethanol and the solution heatedon the steam bath for 10 minutes. The cooled solution was diluted withether, and the solid separted. Following washing with ether, the productwas dried to obtain 13.8 g. (99 percent yield) of product which melted192 194.

2. 2,6-bis -(Phenyl) isonicotinic acid Following the procedure describedin example 1, N- (phenacyl-pyridinium bromide was interacted with 3-benzoyl acrylic acid, ammonium acetate, acetic acid, and aceticanhydride. The yield of 2,6-bis-(phenyl) isonicotinic acid was 63percent following successive crystallizations from ethanol andpropanol-2. The compound melted at 280 282.

Anal. Calcd for C I-1 N0 2 C,. 78.53; H, 4.76; N, 5.09. Found: C, 78.70;H, 4.80; N, 5.28. Example 3. 2,6-bis (4-Fluorophenyl) isonicotinic acidI. 4-(Fluorophenacyl)bromide A solution of 30 g. (0.190) bromine in 15ml ether was added slowly with stirring to a cooled (5) solution of4-fluoroacetophenone (25 g., 0.18 mole) in 25 nil ether and the reactionmixture was stirred at room temperature for 15 minutes. The ethersolution was washed twice with water, then with sodium thiosulfatesolution, I

and finally with water, prior to drying over sodium sulfate. The removalof solvent left 40.6 g. of crude oil which was then distilled to yield31 g. of product boiling at 82 at 0.4 mm. pressure. This product was approximately 94 percent pure and contained small amounts of startingmaterial and dibrominated material. It was, however, quite satisfactoryfor further use.

2. N- (4-Fluorophenacyl) pyridinium bromide The foregoing intermediate,25 g. was interacted with 10 ml. of pyridine in 50 ml. ofethanol toproduce 31 g., 92 percent yield, of the title quaternary salt having amelting point of 208 2l0.

3. 3-(4-Fluorobenzoyl)acrylic acid This intermediate was preparedaccording to the method described by Papa, et al. (loc. cit.).

4. 2,6-bis(4-Fluorophenyl) isonicotinic acid By the method described inmethod 1, N-(4- fluorophenacyl)pyridinium bromide and 3-(4-fluorobenzoyl)-acrylic acid were interacted in the presence of aceticacid, acetic anhydride and ammonium acetate. The desired product, mp278-280, was obtained in 55 percent yield following crystallization fromethanol.

Anal. Calcd for C,,H,,N0,F,; C, 69.45; H, 3.57; N, 4.50; F, 12.21.Found: C, 69.28; H, 3.65; N, 4.63; F, 11.91.

Example 4. 2,6-bis(4-Bromophenyl) isonicotinic acid 1.N-(4-Bromophenacyl)pyridinium bromide This intermediate was preparedfrom 4- bromophenacyl bromide and pyridine after the manner indicatd inExample 1. Following crystallization, it melted at 242244. I

2. 2,6-bis(4-Bromophenyl)isonicotinic acid The foregoing intermediatesand 3-(4-bromobenzoyl)acrylic acid (prepared according to Papa, et a1.loc. cit.) were interacted with ammonium acetate in methanol solution asdescribed in Example 1. Follow ing a 4 hour relux period, the mixturewas filtered and the residual material was digested in hot acetic acidfor a short time. Upon dilution with water, cooling and filtering, acrystalline product resulted. This was collected by filtration, washedwith water and then recrystallized twice from propanol-Z (with use ofcharcoal) to give a 53 percent yield of the title compound, mp 293 295.

Anal. Calcd for C H Br NO z C, 49.92; H, 2.56; Br, 36.90; Found: C,49.92; H, 2.60; Br, 37.07. Example 5. 2,6-bis (3,4-Dichlorophenyl)isonicotinic Acid 1. N(3,4-dichlorophenacyl) pyridinium bromide Asolution of 25 g. (0.09 mole) 3,4-dichlorophenacyl bromide in 150 mlethanol at 65 was added to a solution of 8 g. (0.1 mole) pyridine in 450ml ethanol at 90. The resulting solution was refluxed for ten minutes,then allowed to cool. The crystalline solid product was filterd to yield20 g. of product which melted 232234. The treatment of the concentratedfiltrates with pyridine gave an additional amount of product. The totalyield amounted to 86 percent of that theoretically expected.

2. 3-(3,4-dichlorobenzoyl) acrylic acid A mixture of 125 ml of1,2-di-chlorobenzene and 25 g. (0.26 mole) maleic anhydride was stirredwell and there was added, portion-wise, 70 g. (0.51 mole) anhydrousaluminum chloride powder during a half-hour period, meanwhilemaintaining the temperature at approximately 45. Thereafter, the mixturewas warmed on a steam bath to maintain steady evolution of hydrogenchloride gas. After 4 hours, the reaction mixture was poured over iceand acidified with concentrated hydrochloric acid. There resulted ayellow, gummy solid which was extracted with hot benzene. Upon coolingof the extracts, a yellow crystalline solid formed which wasrecrystallized from benzene (with use of charcoal) to give a 54 percentyield (33 g) of the title acrylic acid, mp 142144. The melting pointagrees with that reported by Papa, et al. (loc. cit.).

3. 2,6-bis (3,4-Dichloropheny1)isonicotinic acidN-(3,4-dichlorophenacyl) pyridinium bromide (1.73 g.),3-(3,4-dichlorobenzoyl) acrylic acid (1.23 g.), ammonium acetate (4 g.),and methanol (10 ml) were refluxed together for 5 hours. Thereafter, themixture was allowed to cool and the resulting beige solid was collectedby filtration. This solid was slurried with methanol and then withdilute acetic acid, and washed with water. There resulted 1.6 g. (78percent yield) of crude product which melted 330332. It wasrecystallized from a mixture of dimethylformamide and water with the useof charcoal to obtain 1.4 g. of product which had the same melting pointbut gave good analy- Anal. Calcd for C H Cl NO C, 52.33; H, 2.20; C]

5. The material was recrystallized from a mixture of ethanol and etherto give 95 percent yield of the desired compound, mp 208 209.

Anal. Calcd for C H Bro N; C, 54.56; H, 4.58; N, 4.55. Found: C, 54.65;H, 4.74; N, 4.38.

2. 3-(4-Methoxybenzoy1)acrylic acid This intermediate was prepared asdescribed by Papa and coworkers (loc. cit.).

3. 2,6-bis(4-Methoxyphenyl)isonicotinic acid Interaction of theintermediate pyridinium salt with the acrylic acid derivative wascarried out in a methanol solution with ammonium acetate as described inExample 5. The resultant isonicotinic acid mp 2l4-217, was obtained in36 percent yield after recyrstalliaati n r asst oac dt Anal. Calcd for CH NO C, 71.63; H, 5.11; N, 4.18. Found: C, 71.73; H, 5.31; N, 4.25.Example 7. 2-(4-Chlorophenyl)-6-phenyl) isonicotinic acid A mixture ofN-phenacylpyridinium bromide (10.8 g., 0.039 mole), 3-(4-chlorobenzoyl)acrylic acid (8.05 g., 0.039 mole), and ammonium acetate (20 g.) wasrefluxed in methanol ml) for 4 hours. Next, hot glacial acetic acid (38ml.) was added and a few drops of water, additionally. The mixture wasallowed to cool to room temperature, whereupon a gray crystallineprecipitate formed. The solid was collected, washed with water, and thendried. It was recyrstallized from propanol-2 to obtain 7.2 g. (61percent yield) of the title isonicotinic acid mp 254 258.

Anal. Calcd for c H ClNo z C, 69.79; H, 3.91; N, 4.52. Found: C, 69.49;H, 4.07; N, 4.44.

Example 8. 6-(4-Bromophenyl)-2-(4-chloropheny1) isonicotinic acid.

The interaction of N-(4-bromophenacyl) pyridinium bromide and3-(4-chlorobenzoyl) acrylic acid with ammonium acetate was carried outin methanol afterthe manner described in Example 7. Followingcrystallization for propanol-2, a 77 percent yield of the titleisonicotinic acid mp 285287 was obtained.

Anal. Calcd for C H Br Cl N0 C, 55.62; H, 2.85; Halogen (as Cl), 18.25;Found: C, 55.40; H, 2.77; Halogen, 18.39. Example 9.2-(4-Chlorophenyl)-6-(4-methoxyphenyl- )isonicitinic acid The reactionof N-(4-chlorophenacyl pyridinium bromide and 3-(4-methoxybenzoyl)acrylic .acid with ammonium acetate in methanol solution wasaccomplished after the manner described in Example 7. The requisite,acid, mp 240-242, was obtained in 69 percent yield.

Anal. Calcd for C H NO Cl: C, 67.16; H, 4.15; N,

4.12; Cl, 10.43. Found: C, 67.34; H, 4.38; N, 4.02; C1,

10.63. Example 10. dichlorophenyl) isonicotinic acid. I

A mixture of N-(4-chlorophenacyl) pyridinium bromide 15.6 g.),3-(3,4-dichlorobenzoyl)acrylic acid (12 g) and ammonium acetate (45 g)in 200 ml of methanol was refluxed for 3 hours. The ammonium salt of thetitle compound precipitated. Following chilling, the mixture wasfiltered. The solid was digested in hot 20 percent aqueous acetic acidfor 15 min. This mixture was cooled, filtered and the crude product soobtained was suspended in 50 ml of hot ethanol, refluxed briefly, cooledand filtered. The solid which was collected amountedto an 81 percentyield (15 g) of produnsymmetrically-substituted isonicitonic2-(4-Chlorophenyl)-6-(3 ,4-

not which melted at 297300. After crystallization from ethanol, theproduct melted at 300.

Anal. Calcd for c,,,i-i,,cl,No C, 57.10; H, 2.64; N, 3.71. Found: C,56.91; H, 2.75; N, 3.65.

Example 1 1. 2-(3,4-Dichlorophenyl)-6-( 4- methoxyphenyl) isonicotinicAcid. The intermediate quaternary salt from Example 6 was caused toreact with 3-(3,4-dichlorobenzoyl)acrylic acid from Example 5,essentially according to the procedure employed for Example 10. Thereresulted thereby an 83 percent yield of product which melted at 245-247.

Anal. Calcd for C H Cl NO C, 60.98; H, 3.50; N, 3.74. Found: C, 61.17;H, 3.75; N, 3.74.

B. alpha-(ALKYLAMlNOMETHYL)-and alpha-( DIALKYLAMINOMETHYL)-2,6-DlARYI.-4- PYRIDINECARBINOLS Example 12. alpha-(Diethylaminomethyl)-2,6-bis-(4- Chlorophenyl)-4-pyridinecarbinol 1.Bromomethyl 2,6-bis-(4-chlorophenyl-4-pyridyl ketone A mixture of2,6-bis-(4-chlorophenyl) isonicotinic acid from Example 1 (5.3 g., 0.017mole) and thionyl chloride (50 ml) was refluxed for 5 hours. The excessof thionyl chloride was largely removed under reduced pressure and thelast traces of that reagent were then removed by azeotropic distillationwith benzene under reduced pressure. A yellow, crystalline acid chlorideresulted which was converted into the diazomethyl ketone by interactionwith an ether solution of approximately 900 mg of diazomethane at Thereaction was allowed to proceed at -l0 for 24 hours, and then themixture evaporated by dryness. The crystallization of the crude productfrom a mixture of ether and petroleum ether gave an 80 percent yield ofthe desired intermediate which melted with decomposition at l40.142. N,

Anal. Calcd for C H N Cl O: C, 61.97; H, 3.01; N, 11.41. Found: C,61.30; H, 3.20; N, 11.44.

The foregoing diazomethyl pyridyl ketone (g.; 0.011 mole) was suspendedin ether (100 ml) and cooled; to it there was added ml of 48 percenthydrobromic acid meanwhile stirring and cooling in an ice bath. After 2hours, the mixture was diluted with water, and the ether layer wasseparted. The aqueous layer was rendered alkaline with sodium carbonateand then extracted with ether, and neutralized with aqueous sodiumcarbonate solution. Thereafter, the ether solution was dried overpotassium carbonate, filtered, charcoaled, filtered and thenconcentrated to give a crystalline solid. The crude bromomethyl ketonethus obtained was recrystallized from ethanol to give 4.9 g. (90 percentof product) which melted 147149.

2.alpha-(Diethylaminomethyl)-2,6-bis-(4-chlorophenyl)-4-pyridinecarbinol.

A solution of the foregoing bromomethyl ketone (4.9 g.) was prepared in.100 ml of ethylene glycol monoethylether and chilled to 5. Then therewas added a solution of 700 mg. sodium bromohydride in about 2 m1 ofwater. After 4 hours, the stirred reaction mixture was treated with 200ml of water. The mixture was extracted well with ether. The etherextracts were dried over sodium sulfate and the ether was evaporated togive the epoxide containing a little (10 percent) bromohydrin. Thiscrude material was then refluxed with a solution of 7 ml diethylamine in25 ml of ethanol for 3 hours. Following removal of the solvent andexcess amine'under reduced pressure, the residue was taken up in ether.The ether solution was washed with water and dried. Ether solution ofthe desired free base was then treated with a solution of hydrogenchloride in propanol2. The precipitated hydrochloride salt was collectedand recrystallized from a mixture of ethanol and ether. There wasobtained a 42 percent yield of the title compound in the form of thehydrochloride salt, mp 236238.

Anal. Calcd for C H Cl N O: C, 61.14; H, 5.58; N, 6.20; Cl, 23.54.Found: C, 60.95; H, 5.71; N, 6.05; Cl, 23.41.

Example 13. alpha-(Dimethylaminomethyl)-2,6-bis(4-chlorophenyl)-4-pyridinecarbinol Crude epoxide (2.6 g), prepared asdescribed in Example 12 was added to a solution of 2 ml of dimethylaminein 20 ml of ethanol and the solution was refluxed for 3 hours. It wasnecessary to add additional amine (12 ml) and the mixture was thenrefluxed for several hours further owing to the escape of the volatiledimethylamine from the reaction mixture. The reaction mixture was thenworked up according to that procedure given in example 12 and convertedinto the hydrochloride salt, which was a brown solid. This wascrystallized successively from a mixture of ethanol and ether and fromacetone to give 900 mg (28 percent) of the title compound in the form ofits hydrochloride salt, mp 222-223.

Anal. Calcd for C H Cl N O: C, 59.52; H, 5.00; N, 6.61. Found: C, 59.20;H, 5.19; N, 6.50. Example 14. alpha-(Di-n-propylaminomethyl)-2,6-bis(4-chlorophenyl) -4-pyridinecarbinol Crude epoxide (2.2 g), preparedaccording to Example l2, and 6 ml of di-n-propylamine in 25 ml ofethanol were refluxed for 10 hours. The procedure given in Example 12was followed and the crude material was converted to the hydrochloridesalt. Upon crystallization of this from ethanol, there was obtained 1.4g (63 percent) of the desired salt, mp 250-25 2.

Anal. Calcd for C H Cl N O: C, 62.57; H, 6.09; N, 5.84; Cl, 22.17.Found: C, 62.56; H, 6.28; N, 5.86; Cl, 19.82.

Example 15. alpha-(n-Butylaminomethyl)-2,6-bis-(4- Chlorophenyl)-4-Pyridinecarbinol Crude epoxide (5.5 grams) from example 12 wasrefluxed in 200 ml of ethanol which contained 3 ml of nbutylamine for 18hours. The solvent and excess amine were removed under reduced pressure.This residual solid was slurried in ether, then filtered, and finallyrecrystallized from propanol-2. There resulted 2.85 g. (42 percent) ofthe title compound as the free base, mp 169-171.

Anal. Calcd for C H ,Cl NO: C, 66.51; H, 5.82; N, 6.74; Cl, 17.07.Found: C, 66.72; H, 6,03; N, 6.84; Cl, 16.90.

Example 16. alpha-(sec. -Bu'tylaminomethyl)-2,6-bis- (4-Chlorophenyl)-4-Pyridinecarbinol I The epoxide prepared according to Example 12 wasinteracted in ethanol solution with sec. butylamine after the proceduredescribed in Example 20. The product was crystallized from a mixture ofacetonitrile and ethanol. A 61 percent yield of product which melted224-225 resulted therefrom.

Anal. Calcd for C H N Cl O: C, 61.27; H, 5.37; N,

6.21. Found: C, 61.08; H, 5.52; N, 6.02.

Example 17. alpha-(1-Adamantylaminomethyl)-2,6- bis-( 4-Chlorophenyl)-4-Pyridinecarbinol l-Aminoadamantane and the requisite epoxide fromexample 12 were refluxed in ethanol solution for 18 hours. The resultingproduct was recrystallized from ethanol to give a 37 percent yield ofproduct, mp l82l 83.

Anal. Calcd for C H N Cl O; C, 70.58; H, 6.13; N, 5.68; Cl, 14.37.Found: C, 70.56; H, 5.99; N, 5.48; CI, 14.32.

Example 18. alpha-(di-n-pentylaminomethyl)-2,6-bis- (4-Chlorophenyl)-4-Pyridinecarbinol The method described in Example 12 was applied tothe use of di-n-pentylamine. The requisite compound in the form of itshydrochloride was obtained in 38 percent yield; it melted at 228230.

Anal. Calcd for C29H31Cl3N20: C, H, N, 5.23. Found: C, 64.98; H, 6.91;N, 4.96.

Example 19. alpha-(4-heptylaminomethyl)-2,6-bis-(4- Chlorophenyl)-4-Pyridinecarbinol 4-Heptylamine was caused to react with the crudeepoxide as obtained from example 12. The desired compound was isolatedin the form of its hydrochloride salt which, following recrystallizationfrom a mixture of ethanol and acetonitrile, was obtained in a yield of63 percent mp 196198.

Anal. Calcd for C H N Cl O: C, 63.22; H, 6.33; N, 5.67. Found: C, 63.19;H, 6.50; N, 5.48. Example 20. alpha-(Methyl-n-butylaminomethyl)-2,6-bis-(4-Chlorophenyl)-4-Pyridinecarbinol The crude epoxide described inExample 12 was interacted with methyl-n-butylamine in refluxing ethanolsolution for 18 hours. The solution was evaporated and the free base wastransformed into its hydrochloride salt. The salt was recrystallizedfrom a mixture of acetp nitrile and ethanol. The yield of product, mp223224, was 63 percent.

Anal. Calcd for C H N CL O: C, 61.88; H, 5.84; N, 6.01. Found: C, 61.55;H, 5,73; N, 5.86.

Example 21. alpha( Methyl-sec.-butylaminomethyl)-2,6-bis-(4-Chlorophenyl)-4-Pyridinecarbinol Methyl-sec. -butylamine andthe epoxide from Example 12 were reacted as described in Example 12.Following crystallization from a mixture of ethanol and ether, the pureproduct, as the hydrochloride salt, was obtained in 68 percent yield, mpl85-l88.

Anal. Calcd for C H N Cl O: C, 61:88; H, 5.84; N, 6.01. Found: C, 61.61;H, 6.20; N, 5.72.

Example 22. alpha-(Methyl-iso-butylaminomethyl)-2,6-bis-(4-chlorophenyl)-4-pyridinecarbinol.

The epoxide from Example 12 and methyl isobutylamine'were refluxed inethanol for 20 hours. The hydrochloride salt of the desired compound, mp220-222, was isolated in 30 percent yield following crystallization frompropanol-2. I

Anal. Calcd for C H N C L O: C, 61.88; H, 5.84; N, 6.01. Found: C,62.07; H, 6.09; N, 5.92. i

Example 23. alpha-(Di-n-butylaminomethyl)-2,6-bis- (4-fluorophenyl)-4-pyridinecarbinol l. Bromomethyl 2,6-bis (4-fluorophenyl)-4-pyridylketone The procedure described in Example 12 was followed. 2,6-bis(4-Fluorophenyl) isonicotinic acid prepared in Example 3 was transformedinto the acid chloride. Following crystallization from benzene, it hadmp 180-l82. The acid chloride was then interacted with diazomethane inether solution. There was obtained a 98 percent yield of crudediazoketone, mp 160-% i0 (wTli decomposition), after recrystallizationfrom ether. Following the procedure employed in Example 1, thediazoketone was converted into the required intermediate bromomethyl ketoiie by treatment with hydrobromic acid. The crude productwasrecrystallized from propanol-2 to produce a 74 per-- A suspension ofthe foregoing bromomethyl ketone (5.0g, 0.013 mole) in 150 ml ethanol at5 was treated with a solution of 500 mg. sodium borohydride in 20 ml ofwater. The suspension was stirred at room temperature for 2.5 hours.Most of the ethanol was removed under reduced pressure, water (ml) wasadded to the residue and the pH was adjusted to approximately 2 to 3 bythe addition of dilute hydrochloric acid. The solid (4.1 g.) whichresulted was collected and treated further with a solution of sodiummethoxide in methanol to yield crude epoxide free from bromohydrin.

The resulting epoxide (3.5 g.) was added to di-nbutylamine (20 ml)ethanol ml) and the mixture was heated on a steam bath for 17 hours.Excess of solvent and reagent were removed under reduced pressure andthe oily residue was taken up in ether, washed (water) and dried oversodium sulfate. The ether solution of the desired base was convertedinto the hydrochloride salt by bubbling hydrogen chloride gas into thesolution. The crude product was crystallized from a mixture of methanoland water to give 2.4 g. (45 percent) of the hydrochloride salt mp228-230.

Anal. Calcd for C H N OF Cl: C, 68.27; H, 7.00; N, 5.90; F, 8.00. Found:C, 68.42; H, 6.91; N, 5.94; F, 7.90. Example 24.alpha-(Di-n-heptylaminomethyl)-2,6-bis (4-Fluorophenyl)-4-Pyridinecarbinol The intermediate epoxide obtained in crude form according to Example 23 was caused to react with di-nheptylamine inethanol after the method employed in Example 12. Following work-up,there was obtained crude hydrochloride salt which melted at -190.Recrystallization from hot ethanol afforded the pure compound as a whitecrystalline solid, mp l93195.

N, 501; F, 6.80. Found: C, 70.76; H, 8.10; N, 4.91; F, 6.72.

Example 25. alpha-(Diethylaminomethyl)-2.6-bis-(4-Bromophenyl)-4-Pyridinecarbinol l. Bromomethyl2,6-bis-(4-bromophenyl)4-pyridyl ketone 2,6-bis-(4-bromophenyl)isonicotinic acid (from Example 4) was converted to the acid-chloride byinteraction with thionyl chloride asdescribed in Example 12. The productwas crystallized from a mixture of benzene and petroleum ether. Theyield of product, mp 156-**, was 96%. The acid chloride in methylenechloride solution was treated with an ether solution of excessdiazomethane. Following the usual procedure, there was obtained a 70percent yield of the diazomethyl ketone, mp l55l57(decomposition)following a crystallization from a mixture of methylene chloride andpetroleum ether. The intermediate diazoketone was converted to thebromomethyl ketone intermediate by treatment with concentratedhydrobromic acid. The crude product, mp l69-l71 was obtained in 92percent yield. Two crystallizations from a mixture of benzene andpetroleum ether provided analytically pure material, mp l71172.

Anal. Calcd for C H Br No: C, 44.74; H, 2.37; Br 47.00. Found: C, 45.03;H, 2.67; Br, 46.81.

2. alpha-(Diethylaminomethyl)-2,6-bis-(4-bromophenyl)-4-pyridinecarbinolThe foregoing bromoketone was reduced in ethanol solution at roomtemperature using sodium borohydride, much after the procedure describedin Example 23. The resulting crude epoxide was interacted withdiethylamine such as described for dibutylamine in Example 23. Thedesired compound was recrystallized thrice from a mixture of ethanol andether to give pure compound, mp 232233.

Anal. Calcd for C H Br ClN O: C, 51.09; H, 4.66; N, 5.18. Found: C,51.18; H, 4.88; N, 5.09.

Example 26. alpha-(Di-n-butylaminomethyl)-2,6- bis(4-bromophenyl)-4-pyridinecarbinol The method applied in Example 25 was used for thesynthesis of this compound. The yield of product from the interaction ofthe requisite secondary amine with the intermediate expoxide was66percent. The hydrochloride salt so obtained melted at 233234,following crystallization from a mixture of methanol and ethanol.

Anal. Calcd for C H Br ClN O: C, 54.33; H, 5.57; N, 4.69. Found: C,54.34; H, 5.61; N, 4.63.

Example 27. alpha-(n-Heptylaminomethyl)-2,6- bis(4-bromophenyl)-4-pyridinecarbinol.

The procedure employed in the previous two examples was used for theinteraction of the epoxide with the required secondary amine. Thehydrochloride salt isolated had mp 208209.

Anal. Calcd for C H Br ClN O: C, 58.20; H, 6.66; N, 4.05. Found: C,58.11; H, 6.70; N, 4.05.

Example 28. alpha-(Di-n-butylaminoethyl)-2,6-bis-(4-methoxyphenyl)-4-Pyridinecarbinol l. Bromomethyl2,6-bis-(4-methoxyphenyl)-4- pyridyl ketone 2,6-bis-(4-methoxyphenyl)isonicotinic acid was synthesized as given in example 6, this wasconverted to its acid chloride by interaction with thionyl chloride. Thecrude acid chloride hydrochloride was used directly for reaction withdiazomethane following the procedure described in Example 23. It wasnecessary to purify the resulting diazomethyl 2,6-bis(4methoxy-phenyl)-4- pyridyl ketone by chromatography over silica gel.Elution with benzene gave some of the ethyl ester of the intermediateacid (mp 99-x); upon changing the eluant to benzene and propanol-2(in aratio of 99:1 by volume) the diazoketone was obtained with mp 99-102 andacceptable ($0.3 percent) elemental analysis in carbon, hydrogen andnitrogen. This was used directly for conversion into crude bromomethylketone by refluxing with hydrobromic acid.

2. alpha-(Di-n-butylaminomethyl)-2,6-bis-(4-methoxyphenyl)4-pyridine-carbinol The above crude bromomethyl ketone wasreduced inethoxyethanol with sodium borohydride much as described inExample 23. The crude epoxide was treated with di-n-butylamine inethanol solution (cf. Example 23) to obtain a 32percent yield of thehydrochloride of the desired carbinolamine. The purified material,recrystallized from propanol-2, melted at 215-2l6.

Anal. Calcd for C H N O Cl; C, 69.79; H, 7.88; N, 5.61; CL, 7.10. Found:C, 69.88; H, 8.05; N, 5.64; Cl, 7.34.

Example 29. alpha-(Di-n-butylaminomethyl)-2,6-bis- (3,4-Dichlorophenyl)-4-Pyridinecarbinol l.2,6-bis-(3,4-dichloropheny1)isonicotinic Chloride-2,6-bis-(3,4-dichlorophenyl) isonicotinic acid (4.4g. 11 mmole) fromExample 5 was mixed with thionyl chloride (20ml) and refluxed for 4hours. Excess thionyl chloride was removed by azeotropic distillationwith benzene under reduced pressure. The resulting crude yellow solidwas recrystallized from benzenepetroleum ether to give 4.0 g (88percent)of material, mp 196198, containing 40.70 percent chlorine vs. 41.08percent calculated.

2. Diazomethyl 2,6-bis(3,4-dichlorophenyl)4-pyridyl Ketone The aboveacid chloride (7.4g, 0.017 mole) was added in small portions over a 30min period to a cold (0-5) solution of diazomethane (5g, 0.12 mole) inether (300 ml). The heterogeneous mixture was stirred for 5 hours at 0and stored overnight in'an ice bath. Excess diazomethane and solventwere removed under reduced pressure. There was obtained 7.4g (98 percentof the title compound, mp 155-158(dec.).

3. Bromomethyl 2,6-bis-(3,4-dichlorophenyl)-4- pyridyl Ketone A solutionof the above diazoketone (3.5 g, 7.8mmole) in methylene chloride (200ml) was added dropwise to a mixture of hydrobromic acid (8ml, 48percent) and methylene chloride (100 ml). The mixture was stirred for 1hour and filtered. The filtratewas washed successively with water,dilute sodium bicarbonate and dried (Na SO Removal of the solvent underreduced pressure gave a brownish-yellow crystalline solid. Afterrecrystallization from chloroformisopropanol, there was obtained 2.8 g(71 percent) of product, mp 189-191.

Anal. Calcd for C H BrChNo: C, 46.57; H, 2.06. Found: C,46.81; H, 2.30.V

4. alpha-( di-n-butylaminomethyl )-2,6-bis-( 3 ,4-dichlorophenyl)-4-pyridinecarbinol The above bromomethyl ketone (1 g, 2mmole) was suspended in ethanol (40 ml). Sodium borohydride mg) wasadded and the mixture was stirred for 1 hour at room temperature. Dilutehydrochloric acid was added to decompose excess borohydride. The mixturewas neutralized with sodium bicarbonate. Water (30 ml) was added and themixture was filtered. The collected solid was washed with water (X2,20ml) and dried under reduced pressure. There was obtained 800 mg (95percent) of crude epoxide, mp l38-145, whlclic ontamed a5out 5 percentof the bromohydrin by analysis.

The crude oxide (1.5 g, 3.7 mmole) from two runs was added to a solutionof di-n-butylamine (5 ml) and ethanol (25 ml). The mixture was refluxedfor 3 hours. Solvent and excess amine were removed under reducedpressure. The residual oil was dissolved in ether and treated with asaturated solution of hydrogen chloride in isopropanol. Thehydrochloride salt was collected by Acid 7 filtration, washed with etherand crystallized from ethanol to afford 1.5 g (71 percent) of the titledcompound, mp 220222.

Anal. Calcd for C H Cl N O: C, 56.22; H, 5.41; N, 486; C1, 30.73. Found:C, 56.11; H, 5.72; N, 4.71; Cl, 30.92. g

5. alpha-N-Oxo-(di-n-butylaminomethyl)-2,6-bis- (3,4-dichlorophenyl)-4-pyridinemethanol Hydrochloride To a solution of a-di-n-butylaminomethyl-2,6-bis 3,4-dichlorophenyl)-4-pyridinemethanol(2.4 g, 4.5 mmole) in ether 100 ml) was added 40 percent peracetic acidin acetic acid (Sml). The reaction mixture was stirred at roomtemperature for 2 hours. During this time, a precipitate formed/Themixture was filtered to yield a solid (1.8 g) which is believed to bethe acetic acid salt of the N-oxide. The solid was slurried in methanoland a few drops of concentrated HCl was added. The solid dissolved andwater was added until no more solid formed. The mixture was filtered andthe solid product was recrystallized from ethanol to give the targetcompound (0.8 g, 33 percent), mp 174175.

Anal. Calcd for C 1-1 N O Cl C, 54.70;H, 5.27; N, 4.72; O, 5.40. Found:C, 54.68; H, 5.24; N, 4.67; O, 5.50.

6. Alternative Procedure Alternatively, 2,6-bis-(3,4-dichlorophenyl)isonicotinic acid can be converted to the active antimalarial agent,a-di-n-butylaminomethyl-Z,6-bis-3,4-dichlorophenyl)-4-pyridinecarbinol,by methods other than that described, and which avoids the use ofdiazomethane, a hazardous reagent not suitable for large scalepreparations.

Diethyl ethoxymagnesiummalonate, prepared by the procedure of'l-LG.Walker and C. R. Hauser, J. Am. Chem. Soc., 68, 1386 (1964), wasdissolved in tetrahydrofuran and added slowly to a refluxing slurry of2,6- bis-(3,4-dichlorophenyl)isonicotinic acid chloride in ether. After2 hours the mixture was poured into a slurry of ice and dilute sulfuricacid. The ether layer was removed and the aqueous layer was extractedfurther with ether. The combined ether extracts were washed with sodiumbicarbonate, and with water and acid per gram of the malonate. After 25minutes the,

product was poured over ice. The resulting yellow solid was extractedwith chloroform and the chloroform removed to yield 32 percent of thebromoethyl 2,6-bis- (3,4-dichlorophenyl)-4-pyridyl ketone, mp 187 190The latter bromoketone was then converted to alphadi-n-butylaminomethyl)-2,6-bis-( 3 ,4-dichlorophenyl)-4-pyridinecarbinol, the targetantimalarial compound, in the same manner as described above inparagraph 4. Example 30. alpha-(Diethylaminomethyl)-2,6-bis-(3,4-dichlorophenyl)-4-Pyridinecarbinol This crude epoxide from Example 29was interacted with a solution of diethylamine in ethanol in the samemanner as in Example 29. There resulted 63 percent yield of thehydrochloride of the desired carbinolamine. This compound had mp 245247following recrystallization from ethanol.

Anal. Calcd for C l-l Cl N O: C, 53.05; H, 4.45; N, 5.38,Cl, 34.05.Found: C, 52.86; H, 4.41; N, 5.47; Cl,

34.05. Example 31. alpha-(Di-n-heptylaminomethyl)-2,6-bis- (3,4-Dichlorophenyl )-4-Pyridinecarbinol The crude epoxide from Example 29was interacted with di-n-heptylamine in ethanol solution in the usualmanner. The hydrochloride of the carbinolamine product melted 210212following recrystallization fro ethanol. The yield was 41 percent.

Anal. Calcd for C H CI N O: C, 59.96; H, 6.56; N, 4.24; Cl, 26.82.Found: C, 60.01; H, 6.61; N, 4.19; Cl,

. Example 32. alpha-(Di-n-butylaminomethyl)-2-(4-Chlorophenyl)-6-Phenyl-4-Pyridinecarbinol 1. Bromomethyl2c4-chlorophenyl)-6-phenyl-4- pyridyl ketone 2-(4-chlorophenyl)-6-phenylisonicotinic acid (from Example 7 was converted to its acid chloride inthe standard way. This intermediate was obtained in 65 percent yield andhad mp 112-ll5.. The crude acid chloride thus obtained was convertedinto the diazoke- 'tone by interaction in the usual manner withdiazomethane, The crude yellow oil was identified and interacted,without purification, with hydrobromic acid to yield the intermediatebromomethyl ketone, mp 102l05, in 77 percent yield afterrecrystallization from ethanol. 7

Anal. Calcd for C l-l BrClNO: C, 59.01; H, 3.39; N, 3.62. Found: C,58.85; H, 3.63; N, 3.70.

2. alpha-(Di-n-butylaminomethyl)-2-(4-chlorophenyl)-6-phenyl-4-pyridinecarbinol.

The intermediate bromoethyl ketone was reduced with sodium borohydridein ethanol, to obtain crude epoxide contaminated with a small amount ofbromohydrin. This was interacted with di-n-butyalmine in ethanolsolution, thereby obtaining the desired compound which was transformedinto'its hydrochloride salt. The yield of the salt was 59percent and hadthe mp of 230232 following crystallization from ethanol.

Anal. Calcd for C l-l Cl N O: C, 68.49; H, 7.24; N, 5,92; C1, 14.98;O,3.38. Found: C, 67.86; H, 7.33; N, 5.80; Cl, 14.99; 0, 3.36.

Example 33. alpha-(Di-n-butylaminomethyl)-6-(4-Bromophenyl)-2-(4-Chlorophenyl)-4-Pyridinecarbinol I 1. Bromomethylchlorophenyl)4-pyridyl ketone The intermediate isonicotinic acid fromExample 8 was transformed in the usual way into the bromomethyl ketone.The intermediate acid chloride melted 141-144 after crystallization froma mixture of benzene and petroleum ether. The diazomethyl ketone ob-'tained therefrom was used directly without purification for interactionwith hydrobromic acid. This intermediate melted 154156.

Anal. Calcd for C l-l Br C1NO: C, 49.01; H, 2.60; N, 3.01. Found: C,49.20; H, 2.87; N, 3.09.

2; alpha-(Di-n-butylaminomethyl)-6-(4- bromophenyl)-2-(4-chlorophenyl)-4-pyridinecarbinol The bromoketone intermediate wastransformed into the oxirane in the customary manner and used withoutpurification in the reaction with di-n-butylamine in ethanol. Thehydrochloride salt of the product was isolated. Followingcrystallization from ethanol, a 71 percent yield (based on bromomethylketone) of the title compound results, mp 236-238.

Anal. Calcd for C H BrCl N O: C, 58.70; H, 6.02; N, 5.07; halogen as Cl,19.26. Found: C, 58.70; H, 6.02; N, 4.86; halogen as Cl, 19.35.

Example 34. alpha-(di-n-butylaminomethyl)-2-(4-chlorophenyl)-6-(4Methoxyphenyl)-4- Pyridinecarbinol 1. Bromomethyl2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4-pyridyl ketone.

The intermediate isonicotinic acid from Example 9 was converted in theusual manner to the acid chloride, mp 104106 and had acceptable (i0.3percent) elemental analysis in carbon hydrogen nitrogen and chlorine.This was transformed into the diazomethyl ketone in the usual manner.The crude intermediate was relatively unstable. Accordingly, this wasimmediately transformed into the bromomethyl ketone by treatment withhydrobromic acid in chloroform solution. Crystallization of thebromomethyl ketone from propanol-2 afforded pure title compound, mp138.5140.5.

Anal. Calcd for C H BrClNO C, 67.65; H, 3.63; N, 3.47; halogen as C1,17.01. Found: C, 67.91; H, 3.84; N, 3.84; halogen as Cl, 16.73.

2. alpha-(Di-n-butylaminomethyl)-2-(4- chlorophenyl)6-(4-methoxyphenyl)-4- pyridinecarbinol The intermediate bromomethylketone was converted into the epoxide in the usual manner and theresulting crude product was reacted directly with di-nbutylamine inethanol. The resulting pyridinecarbinol was converted into thehydrochloride salt which was crystallized from propanol-2. The yield was40 percent of product with mp 224224.5, with decomposition.

Anal. Calcd for C H Cl N O C, 66.79; H, 7.21; N, 5.56; C1, 14.08. Found:C, 66.75; H, 7.40; N, 5.56; Cl,

Example 35. alpha-(Di-n-butylaminomethyl)-2-(4- chlorophenyl-6-(3,4-dichlorophenyl)-4- pyridinecarbinol eld. The pure compound meltedat 136-137 after recrystallization with methylene chloride-ethanol andhad acceptable (:03 percent) elemental analysis in carbon, hydrogen andnitrogen. 1n the usual way, the bromomethyl ketone was converted intothe epoxide and this was used in crude form for reaction with di-nbutylamine. The hydrochloride of the desired compound was isolated and51 percent yield from crude epoxide. The pure compound melted at 216-2l7following recrystallization from propanol-Z.

Anal. Calcd for C27H32Cl4N O: C, H, N, 5,16; Cl, 26.15. Found: C, 59.72;H, 6.05; N, 5.12; Cl, 26.04.

Example 36. alpha-(Di-n-butylaminomethyl)-2-(3,4-dichlorophenyl)-6-(4-methoxyphenyl)-4- Pyridinecarbinol 2-( 3,4-dichlorophenyl )-6-( 4-methoxy-phenyl) isonicotinic acid was obtainedfrom Example 11. This was converted to the acid chloride, and thenceinto the diazomethyl ketone. The purified diazomethyl ketone, mp l07-l08following crystallization from a mixture of ether and petroleum etherwas obtained in 84 percent yield. This intermediate was then treatedwith hydrobromic acid to give a 91 percent yield of the rec tire dintermediate bromomethfiketoneof trip 117- 118. Reduction of theforegoing intermediate with sodium borohydride gave the correspondingepoxide type which was treated with di-n-butylamine in the usual manner.This resulting' product was converted into the hydrochloride of thedesired carbinolamine in 57 percent yield. The compound melted 209-210following crystallization from propanol-2.

' Anal. Calcd for C H C1 -,N,O C, 62.51;H, 6.56; N, 5.21; Cl, 19.77.Found: C, 62.84; H, 6.76; N, 5.24; Cl, 19.76.

C. alpha-(Z-PIPERIDYL)-2,6-DlARYL-4- PYRIDINECARBINOLS Example 37.alpha-(2-Piperidyl)-2,6-bis-(4-Chlorophenyl)-4-Pyridinecarbinol 1.2,6-bis-(4-Chloroplienyl)-4-Pyridyl 2-Pyridyl Ketone A hexane (64 ml)solution of n-butyl lithium (0.1 mole) was mixed with ether ml) and thesolution was chilled to 60 and stirred well. That temperature wasmaintained while 2-bromopyridine (16.0 g., 0.1

mole) was added gradually, and then held at 60 for one hour longer.There was then added 2,6-bis-(4- chlorophenyl)isonicotinic acid (13.76g., 0.02 mole, obtained according to Example 1), and the entire wasstirred at 60 for 2 hours. Thereafter, the solution was poured intoice-water and the product was collected. A yield of 81 percent (13 g.)of the title ketone, mp 18 l-183 was obtained. Recrystallization frompropanol-2gave pure product, mp l86l88.

Anal. Calcd for C H N OCl C, 68.16; H, 3.48; N, 6.91 Cl, 17.50. Found:C, 68.23; H, 3.73; N, 6.80;-Cl, 17.43.

2. alpha-(Z-Piperidyl)-2,6-bis-(4-Chlorophenyl)-4- Pyridinecarbinol Theforegoing intermediate ketone (2.4 g.) was reduced in acidic ethanol mlethanol containing 0.55 ml conc. hydrochloric acid), with platinum(formed by pre-reduction on 150 mg. of platinum oxide) under 40 psighydrogen. After uptake of the requisite amount of hydrogen, the mixturewas filtered and the filtrates was concentrated in vacuo. The base wasliberated by'the addition of 10 percent sodium hydroxide, extracted intoether, the extracts dried, then the solvent removed. The residual basewas chromatographed over silica gel using chloroform and methanol (3:1,v/v) as the eluant. The base was. isolated, then crystallized from amixture of propanol-2 and water to give the pure product, mp 180l8l, in50 percent yield.

Anal. Calcd for C H N Cl o: C, 66.83; H, 5.37; N, 6.78; Cl, 17.15.Found: C, 67.04; H, 5.56; N, 6.76; Cl, 17.02.

D. alpha-( 2-QU1NUCL1D1NYL)-2,6-DlARYL-4- PYRIDENECARBINOLS Example 38.alpha-(2-Quinuc1idinyl)-2,6-bis-(4- chlorophenyl)-4-Pyridinecarbinol l.Ethyl 2, 6-bis(4-chlorophenyl-isonicotinate A solution of2,6-bis-(4-chlorophenyl) isonicotinic acid (15.0 g, 44 mole) in dryethanol (150 ml) containing sulfuric acid (6 ml) was heated to refluxfor 17 hours. The reaction mixture was poured into water (200 ml)containing sodium bicarbonate g). The solution was filtered and theresulting solid recrystallized from benzene to yield the title ester(11.3g, 70

I percent), mp l68-169.

245246(dec). The product can be recrystallized from absolute ethanol.

3. Ethyl N-Benzoyl-3-(4-piperidyl) propionate The title compound wasprepared according to the procedure of Kleinman and Weinhouse, J. Org.Chem. 10, 562 (1945), bp 174 (0.2 mm), reported 184l85 (1mm). The yieldwas 70 percent.

4. 2-(4-Piperidyl)ethyl 2,6-bis-(4-chlorophenyl)-4- pyridyl KetoneHydrochloride To a well-stirred suspension of sodium ethoxide (1.36 g,0.02 mole) in dry toluene (50 ml), a solution prepared from ethyl2,6-bis-4-chlorophenylisonicotinate (4.1 g, 0.011 mole), ethylN-benzoyl-3-(4-piperidyl) propionate (2.89 g, 0.01 mole) and toluene (50ml) was added in a steady stream. The red-brown reaction mixture wasrefluxed with stirring for 2 hours. The toluene, together with theethanol formed during the reaction, were removed by distillation. Fresh,dry toluene (200 ml) was added to the reaction mixture which wasrefluxed for another 6 hours and azeotropic removal of ethanol wasrepeated. The solvent was removed by distillation and the residue wastreated with 18 percent hydrochloric acid (100 ml) and gently refluxedfor 10 hours. The hot suspension was filtered and the filtrate wasconcentrated and made alkaline with percent potassium hydroxidesolution. The free base was extracted with chloroform and the solutionwas dried (1( CO The solvent was evaporated ty yield 1.76 g (41 percent)of free base. A sample was dissolved in ethanol and treated withethanolhydrogen chloride to give a colorless crystalline precipitate ofthe title compound. The salt was recrystallized from ethanol to give mp264-266. Conversion of the free base to the hydrochloride salt wasquantitative.

Anal. Calcd for C H Cl N QH O: C, 60.80; H, 5.53; N, 5.67. Found: C,60.63; H, 5.42; N, 5.76.

5. l-Bromo-2-(4-piperidyl)ethyl 2,6-bis-(4-ch1oropheny1)-4-pyridylKetone Hydrobromide To the warm solution of the preceding ketone (4.39g, 0.01 mole) and hydrobromic acid (48 percent, 50

ml), an equivalent amount of bromine (1.6 g) in hydrobromic acid (16 ml)was added with stirring. The suspension was stirred and held at for 15min. The hydrobromic acid was evaporated under reduced pressure and theresidue was refluxed with acetone (50 ml). The solvent was evaporatedand the residue was suspended in cold water. The precipitate wasseparated and recrystallized from ethanol, 5.3 g percent), mp 256258.

Anal. Calcd for C H Br Cl N O: C, 50.12; H, 4.03; N, 4.68.'Found: C,50.39; H, 4.14; N, 4.68.

6. 2Quinuclidiny1 2,6-bis-(4-chlorophenyl)-4-pyridy1 KetoneHydrochloride The preceding bromoketone (5 g) in chlorofrom ml) wasshaken with aqueous sodium bicarbonate (8 g in 80 ml of water) for 5hours. The chloroform layer was separated and the aqueous layer wasextracted twice with fresh chloroform. The combined extracts were dried(K CO The chloroform was evaporated to leave 3.5 g (90 percent) of thefree base. A sample of the free base (45 mg) was dissolved in chloroformand treated with ethereal hydrogen chloride to give the hydrochloridesalt, 44 mg (91 percent), mp 306-308(dec). The salt was recrystallizedfrom ethanol, mp 308310 (dec).

Anal. Calcd for C H Cl N O: C, 63.37; H, 4.89; N, 5.71. Found: C, 63.10;H, 4.87; N, 5.84.

7. alpha-(2-Quinuclidinyl)-2,6-bis-(4-chlorophenyl)- 4-pyridinemethanolHydrochloride The free base of the preceding ketone (2.2 g) wasdissolved in hot ethanol (80 ml) and treated with an aqueous solution ofsodium borohydride (500 mg in 15 m1 of water). The solution was stirredat room temperature for 2 hours. Most of the ethanol was evaporatedunder reduced pressure. The suspension was diluted with water (20 ml)and acidified with 10 percent hydrochloric acid. After cooling andscratching, a colorless precipitate separated which was collected byfiltration, washed with cold water and dried at 100 overnight (3.2 g, 81percent). The product, mp 200-215 was a mixture of the two possibleracemates. The mixture contained little water as shown by the infraredspectrum.

The crude product was refluxed with acetonitrile (50 ml). The hotsuspension was filtered to yield a solid. The motherliquor was saved forlater suspension of the racemates. The solid (1.7 g, mp 260-265) wasrecrystallized (X3) from a mixture of isopropanol and acetonitrile.After the third recrystallization, the product has mp 268-275.

Anal. Calcd for C H Cl NO: C, 63.10; H, 5.30; N, 5.89. Found: C, 63.09;H, 5.44; N. 5.73.

8. alpha-(2-Quinuclidinyl)-2,6-bis-(4-chlorophenyl)- 4-pyridine-methanolHydrochloride (Racemate A) The foregoing mixture of racemates, mp268-275, recrystallized (X2) from a mixture of ethanol and ether to givemp 295297 (dec), 1.15 g. Thin layer chromatography showed one major spotand the product was considered to be a pure diastereoisomeric pair(Racemate A).

Anal. Calcd for C ,,H Cl NO: C, 63.10; H, 5.30; N, 5.89. Found: C,63.09; H, 5.20; N, 5.85.

Free Base of Racemate A:

Theabove hydrochloride salt (100 mg), was suspended in ether and treatedwith 30 percent aqueous potassium hydroxide. The organic layer wasscparted, dried (K CO and the solvent was evaporated. The

19 colorless, crystalline base was recrystallized from petroleum ether(30-60), mp l30-133 (65 mg). The product was very soluble in ether andchloroform.

Anal. Calcd for C H Cl NO: C, 68,34; H, 5.51; N, 6.37; Found: C, 68.39;H, 5.64; N, 6.l4. 5

alpha-(Z-Quinuclidinyl)-2,6-bis-(4-chlorophenyl)-4- pyridinemethanolHydrochloride (Racemate B).

The acetonitrile solution (mother liquor) from paragraph 7 above wasevaporated to dryness. The residue was recrystallized from hotacetonitrile several times to a constant rn 25926l. A yield was 750 mg.Thin layer chromatography showed one major spot and the product wasconsidered a pure diastereoisomeric pair (Racemate B).

Anal Calcd for C H cl NOz C, 63.10; H, 5.30; N, 5.89. Found: C, 63,26;H, 5.28; N, 6.03.

Free Base of Racemate B.

The hydrochloride salt (60 mg) was suspended in chloroform and shakenwith 30 potassium hydroxide. The organic layer was separated, dried (KCO and the solvent was evaporated The residue was crystallized fromchloroform-petroleum ether, mp 200-202. The product (40 mg) wasessentially insoluble in ether and petroluem ether, but was very solublein chloroform.

Anal. Calcd for C H Cl NO: N, 6.37. Found: N, 6.14.

Mother liquors from all the crystallizations were combined. Solventswere evaporated and the fractional crystallization procedures wererepeated. Additional amounts of Racemates A and B were obtained (100 mgof A and 65 mg of B). Y

CHART 1 Alpha-(Dialkylaminomethyl)-2,6Diaryl-4-Pyridinecarbinols Brapyridine (ArhCOCI-l; (ArhCOCPhBr (AT)5COCH=CHCO2H (ArhCOCHaNB e NILO Ac;MeOH S 0 Cl: CHiNa acid chloride CHzClz )o. 2

(ljocHNz (FOCHzBr i HBr m (Ar)a- (Ar): (Am \N/ (Ar):

CH-CH: CHCHIN R. NH l NaBHr plymc R2 (Ar)@- NJ-(Al'): (Ar)l- N, -(Ar):

Ill

CHART J Alpha-t2-Pipcridyl)-2.G-Diaryl-i-Pyiidylcarbinols Alpha-(241uinuclidinyl)-2,6-Diuryl-4-Pyridinucarbinols and pharmaceuticallyacceptable acid addition salts thereof wherein CHzCH:

\NH R is hydrogen, while CHICH R is hydrogen or lower-alykl NaHCOa H011IBr- 5and R is lower-aklyl, the same or different than R or, wherein RR; is (Cl-1 where R is H;

or, wherein N-CH2 NaBHl HCl l-ICl and (Ar) and (Ar); are substitutedphenyl groupings, either the same or different with a halogen or methoxysubstituent in at least one of the phenyl rings, wherein the compoundsare curative against Plasmedium berghei in mice at a dosage of 640 mg/kgor lower. 2. The compound according to claim 1 wherein (Ar) and (Ar);are the same or different functional groupings which are bothhalogen-substituted phenyl moieties, and salts thereof.

P. berghei screening test (mice) Phototoidcity Activity A MST; test(mice) b dose levels (mg./kg.) Cures, mgJkg. MED; mg./kg.

160 320 1.1;). Oral TABLE I.EVALUATION 0F i-PYRIDYLCARBINOLAMINES gym.0.

Patent A Example 843cc 9 791302822629.6809593 O Q2 3L5 33 fi .&3 2 0 3 00 20 0 0 m A WQZ hly standardized procedure in which the P. bcrgheicauses death of control mice at essentially 6.2 days. An increase insurvival of mice by more than 2.5 found to be statistically significant.Mice W. E. Rothe and D. P. Jacobus,

3. The compound according to claim 1 wherein (Ar)- and (Ar) are the sameor different functional group ings which are both chloroorbromo-substituted phen yl moieties, and salts thereof.

4. The compound according to claim 3 having (Ar) and (Ar) both as4-chloro-phenyl groupings, and salts of said bases.

5. The compound, 2-4-(-bromophenyl)-6-(4-chlorophenyl)-4-alpha-(n-butylamino) methylpyridine carbinol and saltsthereof.

as cured (c). Drugs which prolong the life of the (1 active (:1). ydetermined in mice by the method of J. Med. Chem., 11, 366 (1968).

I Test method described by T. S. Osdcne, I. B. Russell, and L. Rune, J.Med. Chem, 10,

days beyond this time has been b Phototoxicit We claim:

1. Compound of the formula 431 (1967). This test has been made as a higwhich live more than 60 days are regarded mice beyond 14 days areconsidere 23 24 6. The compound 2,6-bis-(4-Chlorophenyl)-4-alpha-2,6-bis-(4-fluorophenyl)-4-pyridinecarbinol. (2-piperidyl)pyridinecarbino] and its salts. 9. The compoundalpha-di-n-butylaminomethyl)-2,6-

7. The compound2,6-bis-(4-chlorophenyl)-4-alphabis-(4-br0mophenyl-4-pyridinecarbinol.(2-quinuclidinyl)pyridine carbinol and its salts.

8. The compound alpha-(di-n-butylaminomethyl)- 5

2. The compound according to claim 1 wherein (Ar)2 and (Ar)6 are thesame or different functional groupings which are bothhalogen-substituted phenyl moieties, and salts thereof.
 3. The compoundaccording to claim 1 wherein (Ar)2and (Ar)6 are the same or differentfunctional groupings which are both chloro-or bromo-substituted phenylmoieties, and salts thereof.
 4. The compound according to claim 3 having(Ar)2 and (Ar)6 both as 4-chloro-phenyl groupings, and salts of saidbases.
 5. The compound,2-4-(-bromophenyl)-6-(4-trifluoromethylphenyl)-2-4(-bromophenyl)-6-(4-chlorophenyl)-4-chlorophenyl)-4-alpha-(n-butylamine)methylpridinecarbinol and salts thereof.
 6. The compound2,6-bis-(4-Chlorophenyl)-4-alpha-(2-piperidyl)pyridine carbinol and itssalts.
 7. The compound2,6-bis-(4-chlorophenyl)-4-alpha-(2-quinuclidinyl)pyridine carbinol andits salts.
 8. The compoundalpha-(di-n-butylaminomethyl)-2,6-bis-(4-fluorophenyl)-4-pyridinecarbinol.9. The compoundalpha-di-n-butylaminomethyl)-2,6-bis-(4-bromophenyl-4-pyridinecarbinol.